Cocaine: Plasma Concentrations After Intranasal Application in Man

Dyke, Craig Van; Barash, P. G.; Jatlow, Peter; Byck, Robert

doi:10.1126/science.56036

Cited by 209 publications

(59 citation statements)

References 13 publications

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“…Moreover, cocaine concentrations that caused contraction of aortic smooth muscles of the ferret (10-6 M to 10-4 M) were fairly comparable with the plasma concentrations reported in cocaine abusers and in cocaine-related deaths. Plasma cocaine levels in those patients is reported to be 0.2-100 Wug/ml (6 X 10-7 to 3 X 10-4 M) (48)(49)(50). However, there are obvious difficulties in comparing the results ofour study with clinical reports ofcocaine-induced cardiovascular events, because there appear to be marked differences among vascular beds ofvarious species in regard to their responsiveness to cocaine (5).…”

Section: Discussioncontrasting

confidence: 39%

Effects of cocaine on excitation-contraction coupling of aortic smooth muscle from the ferret.

Egashira¹,

Morgan

1991

J. Clin. Invest.

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The mechanism by which cocaine alters vascular tone is not fully understood. We determined the effects of cocaine on excitation-contraction coupling of isolated ferret aorta. Cocaine in concentrations < 10-4 M caused a contractile response in a dose-dependent manner. The response of control muscle was significantly larger than that in muscle from ferrets pretreated with reserpine. Cocaine-induced contraction was not affected by endothelial factors, but was significantly inhibited by prazosin 10-7 M pretreatment. The intracellular calcium ([Ca"],), as measured with aequorin, rose in conjunction with cocaine-induced contraction. The degree of contraction generated by 10-4 M cocaine decreased after higher concentrations of cocaine 2 10-M, while aequorin luminescence remained elevated above the levels before 10-6 M cocaine. The dose-response relationships of norepinephrine and sympathetic nerve stimulation were enhanced by 10-M cocaine in control muscles; this did not occur in muscles from reserpine pretreated ferrets. In conclusion, (a) cocaine in concentrations 10-4 M caused vascular contraction presumably by its presynaptic action with consequent alpha-i adrenoceptor activation and consequent ICa++I, rise; (b) high concentrations of cocaine 2 10-3 M reduced muscle tone by decreasing the Ca++ sensitivity of the contractile proteins; and (c) supersensitivity to norepinephrine was mediated by cocaine's action on adrenergic nerve endings. (J. Clin.

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Section: Discussioncontrasting

confidence: 39%

Effects of cocaine on excitation-contraction coupling of aortic smooth muscle from the ferret.

Egashira¹,

Morgan

1991

J. Clin. Invest.

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“…The rationale for choosing the range of cocaine (1-100M) was determined on the basis of reports indicating these concentrations of cocaine in the brains of cocaine abusers after acute intoxication. [22][23][24] To examine whether the mRNA upregulation translated into increased protein expression, HBMECs were treated as described above, followed by cell lysis and subject to Western blotting. As shown in Figure 1C cocaine up-regulated PDGF-BB protein expression in a time-dependent manner, with a peak expression at 12 hours and a gradual decrease thereafter.…”

Section: Cocaine-mediated Up-regulation Of Pdgf Mrna and Protein In Hmentioning

confidence: 99%

Cocaine-mediated induction of platelet-derived growth factor: implication for increased vascular permeability

Yao

Duan

Buch

2011

Blood

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Neuroinflammation associated with advanced HIV-1 infection is often exacerbated in cocaine-abusing, HIV-infected patients. The underlying mechanisms could, in part, be attributed to the increased impairment of blood brain barrier integrity in the presence of cocaine. Plateletderived growth factor (PDGF) has been implicated in several pathologic conditions, specifically attributable to its potent mitogenic effects. Its modulation by drug abuse, however, has received very little attention. In the present study, we demonstrated cocaine-mediated induction of PDGF-BB in human brain microvascular endothelial cells through the binding to its cognate receptor. Furthermore, this effect was mediated, with subsequent activation of mitogen-activated protein kinases and Egr-1 pathways, culminating ultimately into increased expression of PDGF-BB. Cocaine exposure resulted in increased permeability of the endothelial barrier, and this effect was abrogated in mice exposed to PDGF-BB neutralizing antibody, thus underscoring its role as a vascular permeant. In vivo relevance of these findings was further corroborated in cocaine-treated mice that were administered neutralizing antibody specific for PDGF-BB as well as in Egr IntroductionAlthough the advent of combined antiretroviral therapy has significantly decreased the incidence of HIV-associated neurocognitive disorders (HANDs), the prevalence of the disease is actually increasing. Drug abuse has been implicated as a contributing risk factor for increased neuroinflammation associated with HIV-1 infection. Intriguingly, cocaine has been shown to open up the blood-brain barrier (BBB). 1-3 BBB is critical for the maintenance of central nervous system (CNS) homeostasis and for the regulation of the neuronal microenvironment. However, under conditions of barrier disruption as in HIV-1 infection, virus can enter the CNS through infected leukocytes likely via the Trojan horse mechanism.Zhang et al 3 have demonstrated that cocaine-mediated effects on the BBB are complex, including both direct proapoptotic effects on the endothelial cells as well as indirect paracrine effects that are manifested by proinflammatory modulators such as chemokines and cytokines. Cocaine plays a critical role in HIV-1 neuroinvasion, thus accelerating the progression of HAND. [1][2][3] Because the chemokine/growth factor platelet-derived growth factor (PDGF) has been shown in previous reports to be upregulated in the areas around the blood vessels in the brains of macaques with simian immunodeficiency virus infection, 4 we hypothesized that cocaine-mediated disruption of the endothelial barrier could involve PDGF. Adding further validity to this hypothesis was a recent report by Su et al 5 suggesting the role of a novel mediator of the PDGF family as a cerebrovascular permeant in ischemic stroke. Other investigators have also demonstrated the effects of PDGF on endothelial cells. [6][7][8] PDGF comprises a family of proteins that are the products of 4 genes (A-D) that are highly conserved throughout the anim...

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“…The negative inotropic effect which occurs at larger concentrations, appears to be due to Na' channel blocking effects on the sarcolemma and, perhaps, direct interaction with the contractile proteins, would only be clinically relevant for patients consuming very large amounts of cocaine. In some reported pathological series, however, cocaine concentrations in excess of 5 x IO-I M have been found in the blood (Van Dyke et al, 1976;Paly et al, 1982).…”

Section: Toxic Cardiovascular Effects Ofcocainementioning

confidence: 99%

“…Although a wide range of blood levels has been obtained in conjunction with the cardiovascular actions or toxicity of cocaine in man, values usually range from between 10-6 to 5 x 10-M (Van Dyke et al, 1976;Connor & Macleod, 1976;Wetli & Wright, 1979;Paly et al, 1982;Isner et al, 1986;Foltin et al, 1988). On this basis, we selected a cocaine concentration of 10-ms for use in the majority of our experiments.…”

Section: Introductionmentioning

confidence: 99%

The effects of cocaine on intracellular Ca²⁺ handling and myofilament Ca²⁺ responsiveness of ferret ventricular myocardium

Perreault

Hague

Ransil

1990

British J Pharmacology

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1 When ferret right ventricular papillary muscles were stimulated with threshold punctate pulses (0.33 Hz; 30'C), cocaine, 10-M, increased peak tension development from 815 + 120 to 1125 ± 180mg (P < 0.05) and increased the rate of relaxation from peak tension (time to 80% decline from peak tension decreased from 155 + 11 to 144 + 11 ms; P < 0.05). These changes in the twitch were associated with comparable changes in the amplitude and time course of the calcium transient measured with aequorin (amplitude increased from 62 + 4 to 90 + 7% (P < 0.05) of maximal values; time to 80% decline from peak amplitude decreased from 84 + 8 to 64 + 3 ms; P < 0.05). These effects were markedly attenuated in the presence of the 8-adrenoceptor-blocking agent, propranolol, 6 x 10 7M, or by maximization of catecholamine release from the adrenergic nerve endings with field pulses of supratheshold strength, indicating that catecholamine release from the adrenergic nerve endings is responsible for the positive inotropic and lusitropic responses to low and moderate doses of cocaine (i.e., < 10 -I M). 2 High doses of cocaine (i.e., > 10-M) produced negative inotropic and lusitropic effects that were associated with a decreased amplitude and prolonged duration of the calcium transient. 3 In aequorin-loaded intact fibres, cocaine 10-M did not affect the force-calcium relationship unless catecholamines were present. Cocaine, 10-5M, significantly shifted the force-calcium relationship of saponin-skinned muscles (pCa50 = 6.14 + 0.05 versus 5.92 + 0.07; P < 0.05), indicating reduced responsiveness of the myofflaments to calcium. F. (maximal Ca2+-activated force) was reduced to 58% of control in the presence of 10-M cocaine, while the slope of the calcium-force curve remained unchanged. These data indicate that cocaine may also decrease myofilament calcium sensitivity and maximal calciumactivated force, via mechanisms independent of catecholamines, when cellular diffusion barriers are eliminated.

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Cocaine: Plasma Concentrations After Intranasal Application in Man

Cited by 209 publications

References 13 publications

Effects of cocaine on excitation-contraction coupling of aortic smooth muscle from the ferret.

Effects of cocaine on excitation-contraction coupling of aortic smooth muscle from the ferret.

Cocaine-mediated induction of platelet-derived growth factor: implication for increased vascular permeability

The effects of cocaine on intracellular Ca²⁺ handling and myofilament Ca²⁺ responsiveness of ferret ventricular myocardium

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Cocaine: Plasma Concentrations After Intranasal Application in Man

Cited by 209 publications

References 13 publications

Effects of cocaine on excitation-contraction coupling of aortic smooth muscle from the ferret.

Effects of cocaine on excitation-contraction coupling of aortic smooth muscle from the ferret.

Cocaine-mediated induction of platelet-derived growth factor: implication for increased vascular permeability

The effects of cocaine on intracellular Ca2+ handling and myofilament Ca2+ responsiveness of ferret ventricular myocardium

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The effects of cocaine on intracellular Ca²⁺ handling and myofilament Ca²⁺ responsiveness of ferret ventricular myocardium